bims-proarb 2022-05-22 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–05–22
nineteen papers selected by
Rich Giadone, Harvard University

Transcriptional competition shapes proteotoxic ER stress resolution.
Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration.
Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons.
Phase Separation in Regulation of Autophagy.
Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?
Altered Mitochondrial Protein Homeostasis and Proteinopathies.
Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis.
Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology.
Physiological Functions of Intracellular Protein Degradation.
The Role of Extracellular Matrix Components in the Spreading of Pathological Protein Aggregates.
Molecular insights into cell type-specific roles in alzheimer's disease: human induced pluripotent stem cell-based disease modeling.
Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module.
Are mitophagy enhancers therapeutic targets for Alzheimer's disease?
Codon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon.
A real-time pluripotency reporter for the long-term and real-time monitoring of pluripotency changes in induced pluripotent stem cells.
Biological aging processes underlying cognitive decline and neurodegenerative disease.
Hutchinson-Gilford Progeria paves the way for novel targeted anti-aging therapies.
Age-Dependent Effects of Chronic Stress on Zebrafish Behavior and Regeneration.
Fbxw17 is dispensable for viability and fertility in mice.

Nat Plants. 2022 May;8(5): 481-490

Transcriptional competition shapes proteotoxic ER stress resolution.

Dae Kwan Ko, Federica Brandizzi.

Through dynamic activities of conserved master transcription factors (mTFs), the unfolded protein response (UPR) relieves proteostasis imbalance of the endoplasmic reticulum (ER), a condition known as ER stress1,2. Because dysregulated UPR is lethal, the competence for fate changes of the UPR mTFs must be tightly controlled3,4. However, the molecular mechanisms underlying regulatory dynamics of mTFs remain largely elusive. Here, we identified the abscisic acid-related regulator G-class bZIP TF2 (GBF2) and the cis-regulatory element G-box as regulatory components of the plant UPR led by the mTFs, bZIP28 and bZIP60. We demonstrate that, by competing with the mTFs at G-box, GBF2 represses UPR gene expression. Conversely, a gbf2 null mutation enhances UPR gene expression and suppresses the lethality of a bzip28 bzip60 mutant in unresolved ER stress. By demonstrating that GBF2 functions as a transcriptional repressor of the UPR, we address the long-standing challenge of identifying shared signalling components for a better understanding of the dynamic nature and complexity of stress biology. Furthermore, our results identify a new layer of UPR gene regulation hinged upon an antagonistic mTFs-GFB2 competition for proteostasis and cell fate determination.

DOI: https://doi.org/10.1038/s41477-022-01150-w
Sci Adv. 2022 May 20. 8(20): eabn4437

Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration.

Verena Kluever, Belisa Russo, Sunit Mandad, Nisha Hemandhar Kumar, Mihai Alevra, Alessandro Ori, Silvio O Rizzoli, Henning Urlaub, Anja Schneider, Eugenio F Fornasiero.

Aging is a prominent risk factor for neurodegenerative disorders (NDDs); however, the molecular mechanisms rendering the aged brain particularly susceptible to neurodegeneration remain unclear. Here, we aim to determine the link between physiological aging and NDDs by exploring protein turnover using metabolic labeling and quantitative pulse-SILAC proteomics. By comparing protein lifetimes between physiologically aged and young adult mice, we found that in aged brains protein lifetimes are increased by ~20% and that aging affects distinct pathways linked to NDDs. Specifically, a set of neuroprotective proteins are longer-lived in aged brains, while some mitochondrial proteins linked to neurodegeneration are shorter-lived. Strikingly, we observed a previously unknown alteration in proteostasis that correlates to parsimonious turnover of proteins with high biosynthetic costs, revealing an overall metabolic adaptation that preludes neurodegeneration. Our findings suggest that future therapeutic paradigms, aimed at addressing these metabolic adaptations, might be able to delay NDD onset.

DOI: https://doi.org/10.1126/sciadv.abn4437
Curr Biol. 2022 May 10. pii: S0960-9822(22)00671-6. [Epub ahead of print]

Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons.

Jason P Chua, Karan Bedi, Michelle T Paulsen, Mats Ljungman, Elizabeth M H Tank, Erin S Kim, Jonathon P McBride, Jennifer M Colón-Mercado, Michael E Ward, Lois S Weisman, Sami J Barmada.

  Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs), and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not the unrelated phosphatase MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Our findings thus establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell-type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.

Keywords:  RNA stability; TDP-43; autophagosome; iPSCs; induced pluripotent stem cells; macroautophagy; myotubularin; neuronal autophagy; optical pulse labeling; phosphoinositide

DOI:  https://doi.org/10.1016/j.cub.2022.04.053
Front Cell Dev Biol. 2022 ;10 910640

Phase Separation in Regulation of Autophagy.

Yi Lu, Chunmei Chang.



Keywords:  autophagosome formation; autophagy; autophagy substrate; cargo receptor; phase separation; selective autophagy

DOI:  https://doi.org/10.3389/fcell.2022.910640
Mov Disord. 2022 May 17.

Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?

Simone Engelender, Leonidas Stefanis, Salvatore Oddo, Arianna Bellucci.

  Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age-related onset, characterized by the pathological accumulation of aggregated protein deposits. These mainly include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) as well as frontotemporal lobar degeneration (FTLD). The deposition of abnormal protein aggregates in the brain of patients affected by these disorders is thought to play a causative role in neuronal loss and disease progression. On that account, the idea of improving the clearance of pathological protein aggregates has taken hold as a potential therapeutic strategy. Among the possible approaches to pursue for reducing disease protein accumulation, there is the stimulation of the main protein degradation machineries of eukaryotic cells: the ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Of note, several clinical trials testing the efficacy of either UPS- or ALP-active compounds are currently ongoing. Here, we discuss the main gaps and controversies emerging from experimental studies and clinical trials assessing the therapeutic efficacy of modulators of either the UPS or ALP in neurodegenerative proteinopathies, to gather whether they may constitute a real gateway from these disorders. © 2022 International Parkinson and Movement Disorder Society.

Keywords:  autophagy lysosomal pathway; neurodegenerative proteinopathies; pathological protein aggregates; therapeutic strategies; ubiquitin proteasomal system

DOI:  https://doi.org/10.1002/mds.29058
Front Mol Neurosci. 2022 ;15 867935

Altered Mitochondrial Protein Homeostasis and Proteinopathies.

Aya Jishi, Xin Qi.

  Increasing evidence implicates mitochondrial dysfunction as key in the development and progression of various forms of neurodegeneration. The multitude of functions carried out by mitochondria necessitates a tight regulation of protein import, dynamics, and turnover; this regulation is achieved via several, often overlapping pathways that function at different levels. The development of several major neurodegenerative diseases is associated with dysregulation of these pathways, and growing evidence suggests direct interactions between some pathogenic proteins and mitochondria. When these pathways are compromised, so is mitochondrial function, and the resulting deficits in bioenergetics, trafficking, and mitophagy can exacerbate pathogenic processes. In this review, we provide an overview of the regulatory mechanisms employed by mitochondria to maintain protein homeostasis and discuss the failure of these mechanisms in the context of several major proteinopathies.

Keywords:  mitochondrial dysfunction; mitochondrial quality control; neurodegeneration; protein homeostasis; proteinopathies

DOI:  https://doi.org/10.3389/fnmol.2022.867935
J Transl Med. 2022 05 14. 20(1): 229

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis.

Manar Elkenani, Amal Z Barakat, Torsten Held, Daniel Marques Rodrigues, Sherok Mobarak, Surabhi Swarnka, Ibrahim M Adham, Belal A Mohamed.

   BACKGROUND: Molecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that Hspa4 deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored.
METHODS: We performed a comparative phenotypic and biochemical analyses of Hspa4 knockout (KO) mice with wild-type (WT) littermates.
RESULTS: HSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. Hspa4-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving Hspa4-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. Hspa4-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62/sequestosome accompanied by increased number of TUNEL-positive nuclei.
CONCLUSIONS: Our findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities.

Keywords:  Autophagy; HSPs; Myopathy

DOI:  https://doi.org/10.1186/s12967-022-03418-3
Sci Rep. 2022 May 17. 12(1): 8140

Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology.

Liberty François-Moutal, David Donald Scott, Andrew J Ambrose, Christopher J Zerio, Marina Rodriguez-Sanchez, Kumara Dissanayake, Danielle G May, Jacob M Carlson, Edward Barbieri, Aubin Moutal, Kyle J Roux, James Shorter, Rajesh Khanna, Sami J Barmada, Leeanne McGurk, May Khanna.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.

DOI: https://doi.org/10.1038/s41598-022-12191-8
Annu Rev Cell Dev Biol. 2022 May 19.

Physiological Functions of Intracellular Protein Degradation.

Erik McShane, Matthias Selbach.

While cellular proteins were initially thought to be stable, research over the last decades has firmly established that intracellular protein degradation is an active and highly regulated process: Lysosomal, proteasomal, and mitochondrial degradation systems were identified and found to be involved in a staggering number of biological functions. Here, we provide a global overview of the diverse roles of cellular protein degradation using seven categories: homeostasis, regulation, quality control, stoichiometry control, proteome remodeling, immune surveillance, and baseline turnover. Using selected examples, we outline how proteins are degraded and why this is functionally relevant. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-cellbio-120420-091943
Front Cell Neurosci. 2022 ;16 844211

The Role of Extracellular Matrix Components in the Spreading of Pathological Protein Aggregates.

Edoardo Moretto, Skye Stuart, Sunaina Surana, Jose Norberto S Vargas, Giampietro Schiavo.

  Several neurodegenerative diseases are characterized by the accumulation of aggregated misfolded proteins. These pathological agents have been suggested to propagate in the brain via mechanisms similar to that observed for the prion protein, where a misfolded variant is transferred from an affected brain region to a healthy one, thereby inducing the misfolding and/or aggregation of correctly folded copies. This process has been characterized for several proteins, such as α-synuclein, tau, amyloid beta (Aβ) and less extensively for huntingtin and TDP-43. α-synuclein, tau, TDP-43 and huntingtin are intracellular proteins, and their aggregates are located in the cytosol or nucleus of neurons. They have been shown to spread between cells and this event occurs, at least partially, via secretion of these protein aggregates in the extracellular space followed by re-uptake. Conversely, Aβ aggregates are found mainly extracellularly, and their spreading occurs in the extracellular space between brain regions. Due to the inherent nature of their spreading modalities, these proteins are exposed to components of the extracellular matrix (ECM), including glycans, proteases and core matrix proteins. These ECM components can interact with or process pathological misfolded proteins, potentially changing their properties and thus regulating their spreading capabilities. Here, we present an overview of the documented roles of ECM components in the spreading of pathological protein aggregates in neurodegenerative diseases with the objective of identifying the current gaps in knowledge and stimulating further research in the field. This could potentially lead to the identification of druggable targets to slow down the spreading and/or progression of these pathologies.

Keywords:  HSPG; TDP-43; alpha synuclein; amyloid beta; extracellular matrix; huntingtin; proteases; tau

DOI:  https://doi.org/10.3389/fncel.2022.844211
Neuroscience. 2022 May 12. pii: S0306-4522(22)00235-4. [Epub ahead of print]

Molecular insights into cell type-specific roles in alzheimer's disease: human induced pluripotent stem cell-based disease modeling.

Wenhui Qu, Peter Canoll, Gunnar Hargus.

  Alzheimer's disease (AD) is the most common cause of dementia resulting in widespread degeneration of the central nervous system with severe cognitive impairment. Despite the devastating toll of AD, the incomplete understanding of the complex molecular mechanisms hinders the expeditious development of effective cures. Emerging evidence from animal studies has shown that different brain cell types play distinct roles in the pathogenesis of AD. Glutamatergic neurons are preferentially affected in AD and pronounced gliosis contributes to the progression of AD in both a cell-autonomous and a non-cell-autonomous manner. Much has been discovered through genetically modified animal models, yet frequently failed translational attempts to clinical applications call for better disease models. Emerging evidence supports the significance of human-induced pluripotent stem cell (iPSC) derived brain cells in modeling disease development and progression, opening new avenues for the discovery of molecular mechanisms. This review summarizes the function of different cell types in the pathogenesis of AD, such as neurons, microglia, and astrocytes, and recognizes the potential of utilizing the rapidly growing iPSC technology in modeling AD.

Keywords:  Alzheimer's disease; Amyloid; Disease modeling; Induced pluripotent stem cells; Tau

DOI:  https://doi.org/10.1016/j.neuroscience.2022.05.006
iScience. 2022 May 20. 25(5): 104282

Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module.

Shivani Patel, Santosh Kumar, Simone Baldan, Arkadi Hesin, Julia Yaglom, Michael Y Sherman.

  The major heat shock protein Hsp70 forms a complex with a scaffold protein Bag3 that links it to components of signaling pathways. Via these interactions, the Hsp70-Bag3 module functions as a proteotoxicity sensor that controls cell signaling. Here, to search for pathways regulated by the complex, we utilized JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3. RNAseq followed by the pathway analysis indicated that several signaling pathways including UPR were activated by JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated, while other UPR branches were not induced, suggesting that the response was unrelated to the ER proteotoxicity and ER-associated kinase PERK1. Indeed, induction of the UPR genes under these conditions was driven by a distinct eIF2α kinase HRI. Hsp70-Bag3 directly interacted with HRI and regulated eIF2α phosphorylation upon cytoplasmic proteotoxicity. Therefore, cytosolic proteotoxicity can activate certain UPR genes via Hsp70-Bag3-HRI-eIF2α axis.

Keywords:  Molecular biology; Molecular interaction; Protein

DOI:  https://doi.org/10.1016/j.isci.2022.104282
Biomed Pharmacother. 2022 May;pii: S0753-3322(22)00307-9. [Epub ahead of print]149 112918

Are mitophagy enhancers therapeutic targets for Alzheimer's disease?

Jangampalli Adi Pradeepkiran, Ashly Hindle, Sudhir Kshirsagar, P Hemachandra Reddy.

  Healthy mitochondria are essential for functional bioenergetics, calcium signaling, and balanced redox homeostasis. Dysfunctional mitochondria are a central aspect of aging and neurodegenerative diseases such as Alzheimer's disease (AD). The formation and accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (P-tau) play large roles in the cellular changes seen in AD, including mitochondrial dysfunction, synaptic damage, neuronal loss, and defective mitophagy. Mitophagy is the cellular process whereby damaged mitochondria are selectively removed, and it plays an important role in mitochondrial quality control. Dysfunctional mitochondria are associated with increased reactive oxygen species and increased levels of Aβ, P-tau and Drp1, which together trigger mitophagy and autophagy. Impaired mitophagy causes the progressive accumulation of defective organelles and damaged mitochondria, and it has been hypothesized that the restoration of mitophagy may offer therapeutic benefits to AD patients. This review highlights the challenges of pharmacologically inducing mitophagy through two different signaling cascades: 1) The PINK1/parkin-dependent pathway and 2) the PINK1/parkin-independent pathway, with an emphasis on abnormal mitochondrial interactions with Aβ and P-Tau, which alter mitophagy in an age-dependent manner. This article also summarizes recent studies on the effects of mitophagy enhancers, including urolithin A, NAD+, actinonin, and tomatidine, on mutant APP/Aβ and mutant Tau. Findings from our lab have revealed that mitophagy enhancers can suppress APP/Aβ-induced and mutant Tau-induced mitochondrial and synaptic dysfunctions in mouse and cell line models of AD. Finally, we discuss the mechanisms underlying the beneficial health effects of mitophagy enhancers like urolithin A, NAD+, resveratrol and spermidine in AD.

Keywords:  Alzheimer’s disease; Aβ; Mitochondrial dysfunction; Mitophagy; Phosphorylated tau

DOI:  https://doi.org/10.1016/j.biopha.2022.112918
Nat Commun. 2022 May 20. 13(1): 2815

Codon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon.

Aviv A Rosenberg, Ailie Marx, Alex M Bronstein.

Synonymous codons translate into chemically identical amino acids. Once considered inconsequential to the formation of the protein product, there is evidence to suggest that codon usage affects co-translational protein folding and the final structure of the expressed protein. Here we develop a method for computing and comparing codon-specific Ramachandran plots and demonstrate that the backbone dihedral angle distributions of some synonymous codons are distinguishable with statistical significance for some secondary structures. This shows that there exists a dependence between codon identity and backbone torsion of the translated amino acid. Although these findings cannot pinpoint the causal direction of this dependence, we discuss the vast biological implications should coding be shown to directly shape protein conformation and demonstrate the usefulness of this method as a tool for probing associations between codon usage and protein structure. Finally, we urge for the inclusion of exact genetic information into structural databases.

DOI: https://doi.org/10.1038/s41467-022-30390-9
Aging (Albany NY). 2022 May 15. 14(undefined):

A real-time pluripotency reporter for the long-term and real-time monitoring of pluripotency changes in induced pluripotent stem cells.

Hong-Fen Shen, Yong-Long Li, Shi-Hao Huang, Jia-Wei Xia, Zhi-Fang Yao, Gao-Fang Xiao, Ying Zhou, Ying-Chun Li, Jun-Wen Shi, Xiao-Lin Lin, Wen-Tao Zhao, Yan Sun, Yu-Guang Tian, Jun-Shuang Jia, Dong Xiao.

  To master the technology of reprogramming mouse somatic cells to induced pluripotent stem cells (iPSCs), which will lay a good foundation for setting up a technology platform on reprogramming human cancer cells into iPSCs. Mouse iPSCs (i.e., Oct4-GFP miPSCs) was successfully generated from mouse embryonic fibroblasts (MEFs) harboring Oct4-EGFP transgene by introducing four factors, Oct4, Sox2, c-Myc and Klf4, under mESC (Murine embryonic stem cells) culture conditions. Oct4-GFP miPSCs were similar to mESCs in morphology, proliferation, mESC-specific surface antigens and gene expression. Additionally, Oct4-GFP miPSCs could be cultured in suspension to form embryoid bodies (EBs) and differentiate into cell types of the three germ layers in vitro. Moreover, Oct4-GFP miPSCs could develop to teratoma and chimera in vivo. Unlike cell cycle distribution of MEFs, Oct4-GFP miPSCs are similar to mESCs in the cell cycle structure which consists of higher S phase and lower G1 phase. More importantly, our data demonstrated that MEFs harboring Oct4-EGFP transgene did not express GFP, until they were reprogrammed to the pluripotent stage (iPSCs), while the GFP expression was progressively lost when these pluripotent Oct4-GFP miPSCs exposed to EB-mediated differentiation conditions, suggesting the pluripotency of Oct4-GFP miPSCs can be real-time monitored over long periods of time via GFP assay. Altogether, our findings demonstrate that Oct4-GFP miPSC line is successfully established, which will lay a solid foundation for setting up a technology platform on reprogramming cancer cells into iPSCs. Furthermore, this pluripotency reporter system permits the long-term real-time monitoring of pluripotency changes in a live single-cell, and its progeny.

Keywords:  Oct4-EGFP transgene; cancer cell reprogramming; cancer therapy; induced pluripotent stem (iPS) cells; pluripotency reporter system

DOI:  https://doi.org/10.18632/aging.204083
J Clin Invest. 2022 05 16. pii: e158453. [Epub ahead of print]132(10):

Biological aging processes underlying cognitive decline and neurodegenerative disease.

Mitzi M Gonzales, Valentina R Garbarino, Erin Pollet, Juan P Palavicini, Dean L Kellogg, Ellen Kraig, Miranda E Orr.

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.

DOI: https://doi.org/10.1172/JCI158453
Med (N Y). 2021 Apr 09. pii: S2666-6340(21)00107-0. [Epub ahead of print]2(4): 353-354

Hutchinson-Gilford Progeria paves the way for novel targeted anti-aging therapies.

Oliver Dreesen, Brian Kennedy.

Hutchinson-Gilford Progeria is an accelerated aging syndrome caused by permanently farnesylated mutant lamin A, termed progerin. Recently, the FDA approved Lonafarnib, a farnesyltransferase inhibitor, to treat progeria, while Koblan and colleagues used novel gene editing methods to target the root cause of this disease by correcting the LMNA mutation.

DOI: https://doi.org/10.1016/j.medj.2021.03.005
Front Physiol. 2022 ;13 856778

Age-Dependent Effects of Chronic Stress on Zebrafish Behavior and Regeneration.

Angie Henríquez Martínez, Laura C Ávila, María A Pulido, Yeferzon A Ardila, Veronica Akle, Natasha I Bloch.

  Stress can have a significant impact on many aspects of an organism's physiology and behavior. However, the relationship between stress and regeneration, and how this relationship changes with age remains poorly understood. Here, we subjected young and old zebrafish to a chronic stress protocol and evaluated the impact of stress exposure on multiple measures of zebrafish behavior, specifically thigmotaxis (open field test) and scototaxis (light/dark preference test), and on regeneration ability after partial tail amputation. We found evidence that young and older adult fish are differentially impacted by stress. Only young fish showed a significant change in anxiety-like behaviors after being exposed to chronic stress, while their regeneration ability was not affected by the stress protocol. On the other hand, older fish regenerated their caudal fin significantly slower compared to young fish, but their behavior remained unaffected after being exposed to stress. We further investigated the expression of two candidate genes (nlgn1 and sam2) expressed in the central nervous system, and known to be associated with stress and anxiety-like behavior. The expression of stress-related gene candidate sam2 increased in the brain of older individuals exposed to stress. Our results suggest there is a close relationship between chronic stress, regeneration, and behavior in zebrafish (Danio rerio), and that the impact of stress is age-dependent.

Keywords:  aging; anxiety; behavior; chronic stress (or “stress”); tissue regeneration; zebrafish

DOI:  https://doi.org/10.3389/fphys.2022.856778
Mol Biol Rep. 2022 May 19.

Fbxw17 is dispensable for viability and fertility in mice.

Zhen Chen, Dupeng Ma, Tingyu Jin, Ziqi Yu, Jiong Li, Qi Sun, Zejia Li, Ziye Du, Rong Liu, Yi Li, Mengcheng Luo.

   BACKGROUND: Skp1-Cullin-F-box (SCF) E3 ligase complex plays an important role in regulating spermatogenesis and fertility in mice. As a member of F-box proteins, the function of F-box and WD-40 domain protein 17 (Fbxw17) during spermatogenesis and fertility is unclear. In this study, we illustrate its function for spermatogenesis and fertility.
METHODS AND RESULTS: Here, we generated the Fbxw17 knockout (KO) mouse model by using the CRISPR/Cas9 system and analyzed the meiotic process and the fertility. Then, our results demonstrated that testis and sperm in the Fbxw17 KO mice had normal morphology. The testis weight, sperm count and fertility of Fbxw17 KO mice showed no significant difference compared with the wild-type mice. Subsequently, histological analysis of Fbxw17 KO mice revealed apparently normal germ cells of all stages and mature spermatozoa. Meanwhile, nuclear spread analysis showed that the synaptonemal complex formation and DSB repair proceeded normally in Fbxw17-deficient spermatocytes. Furthermore, we didn't find defects in the meiotic prophase I spermatocytes and germ cells showed no apparent apoptosis in Fbxw17 KO mice.
CONCLUSIONS: Our results show that Fbxw17 is dispensable for fertility in mice.

Keywords:  F-box protein; Fbxw17; Fertility; Spermatogenesis

DOI:  https://doi.org/10.1007/s11033-022-07512-z